CANDIDA PROTON PUMP--AN IMPORTANT MOLECULAR TARGET

Project Details

Description

Candida albicans is a predominant cause of opportunistic fungal
infections in HIV-infected individuals. These infections can be present
as topical infections which are readily treated with existing antifungal
drugs or as disseminated infections which are extremely difficult to
treat and result in mortality rates exceeding 50%. The treatment of
disseminated disease often requires the use of the highly toxic drug
amphotericin B. Other less toxic drugs ar available, such a s
fluconazole, but their efficacy is unproven. There is an urgent need to
develop highly specific antifungal directed at new molecular target. In
this application, we propose to develop the proton pumping plasma
membrane H+-ATPase of Candida Albicans as a target for a new class of
antifungal agents. The H+-ATPase is an attractive target because it is
an essential enzyme that represents 20-40% of the total plasma membrane
protein and it has extracellularly expose regions that when modified
attenuate its catalytic activity. In addition, the H+-ATPase is believed
to play an important role in the pathogenicity of Candida through its
effects on intracellular pH regulation, nutrient uptake, and medium
acidification. Most importantly, an opportunity exists to jump start the
drug discovery program and quickly develop lead compounds because of the
discovery that omeprazole (Losec), a clinically-important anti-ulcer
drug, which inhibits the gastric H+,K+-ATPase, blocks, Candida cell
growth and is a potent inhibitor of the fungal H+-ATPase. ASTRA Hassle
AB, the developer of omeprazole, has agreed to provide us with
substituent analogy of omeprazole and other anti-ulcer drugs, like
SCH28080, for specific anti-H+-ATPase reagent that can progress to
clinical trials. The drug discovery program has been designed to permit
efficient screening of compounds for anti-H+-ATPase activity. All
initial screens will be established with a Saccharomyces strain
expressing a hybrid Candida-Saccharomyces PMAI gene to allow the
biochemistry and genetics of the Saccharomyces system to be exploited.
Whenever possible, correlative experiments will be performed with Candida
albicans. The drug discovery program will evaluate the mechanistic
action of lead compounds thought biochemical and genetic analyses.
Finally, the role of the H+-ATPase in dimorphism, which has been linked
to pathogenicity, will be evaluated by the application of highly specific
lead compounds as they arise, as well as by genetic manipulation of PMAI
in Candida albicans and in a pseudohypha Saccharomyces model.
StatusFinished
Effective start/end date12/1/9311/30/96

Funding

  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health

ASJC

  • Medicine(all)
  • Immunology and Microbiology(all)

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